Description:FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10; Rule 13]

TITLE: “TRANSDERMAL DRUG DELIVERY PATCH AND METHOD FOR THE MANUFACTURE OF AN ADHESIVE MONOLITHIC PRESSURE-SENSITIVE LAYER”

Name and Address of the Applicant:
Health Diary Pvt Ltd.
SY -252 FP-84/B PLOT-A TPS-5,
B/S CHANDRA PRBHADIGAMBER TEMPLE, PARLE POINT, SURAT- 395007

Nationality: Indian

The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE OF THE INVENTION

TRANSDERMAL DRUG DELIVERY PATCH AND METHOD FOR THE MANUFACTURE OF AN ADHESIVE MONOLITHIC PRESSURE-SENSITIVE LAYER

BACKGROUND

Technical Field
[0001] The inventive subject matter presented herein is generally directed toward a transdermal drug delivery patch. More particularly, embodiments are related to but are not limited to a method for the manufacture of an adhesive monolithic pressure-sensitive layer. The present invention also relates to an abuse-deterrent transdermal patch for the transdermal administration of Paracetamol. The present invention also relates to processes for the preparation of the transdermal patches defined herein, as well as to the use of these transdermal drug delivery patches for the treatment of fever/moderate pain.

Description of the Related Art
[0002] The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also be inventions.
[0003] Typically, acetaminophen (paracetamol, APAP) is one of the most widely used medications and particularly in adults, infants, and children. Its antipyretic and analgesic efficacy has been established in many placebo-controlled clinical trials in adults and children. Oral administration of APAP is the most common route for this drug in populations of all ages. However, the oral route of APAP administration may not be practical in adults from either a clinical or pharmaceutical perspective. Therefore, an alternative route of administration may be most useful for adult use.
[0004] Usual APAP doses are 325- 1000 mg/ dose and up to 4000 mg daily in adults, and 10- 15 mg/ kg/ dose every 4- 6 hours up to five times/ day for not more than 5-10 days in children and infants, or 1.5 g/ square meter body surface area/ day, in divided doses. APAP is available for oral administration in liquid and tablet forms, and also for rectal administration (although absorption by this route is variable). An oral sustained­ released preparation of APAP has been marketed recently in the United States for pediatric use.
[0005] US patent US8273405B2 discloses a water-absorbent adhesive composition that contains adhesive composition that is water-insoluble. The adhesive composition adheres well to moist surfaces. Even after absorbing a large amount of water, e.g., greater than 15 wt.%, adhesive composition adheres well to moist surfaces. This invention also provides a method for the preparation of a water-soluble adhesive composition.
[0006] PCT application WO0209763A2 discloses the preparation of transdermal delivery systems for drugs that requires alcohol for the dissolution and the invention describes utilizing water-miscible tetraglycol in the place of the standard alcohols. The invention also discloses an alcohol-miscible drug comprising an alcohol-miscible drug with water-miscible tetraglycol and water for the dissolution of the drug in the form of a hydrogel.
[0007] US patent US6689399B1 discloses transdermal delivery of an anti-inflammatory composition for the treatment of joint and muscle pain. The invention discloses transdermal delivery of a capsacinoid, a primary amine selected from glucosamine and galactosamine and carrier. The invention describes a capsacinoid and glucosamine at a high concentration and works together synergistically to prevent the prolonged effect of pain relief.
[0008] Matrix-type patches of paracetamol using blends of Xanthan gum and HPMC K4M with PEG-400 as a plasticizer are disclosed in the scientific article. Linseed oil and oleic acid were used to get better permeation enhancer effects. In all the developed formulations, HPMC K4M and Linseed oil combination showed faster release of paracetamol in vitro diffusion study. (Gorle, A. P., International Research Journal of Pharmacy, 2016, 7(3):30-34).
[0009] Acetaminophen-induced hepatotoxicity is a common consequence of acetaminophen overdose and may lead to acute liver failure (ALF). Currently, acetaminophen is the most common cause of ALF in both the United States and the United Kingdom, with a trend of increasing incidence in the United States. N-acetylcysteine is the most effective drug to prevent progression to liver failure with acetaminophen hepatotoxicity. Liver transplantation is the only definitive therapy that will significantly increase the chances of survival for advanced ALF. This communication reviews current information regarding the causes and management of acetaminophen-induced hepatotoxicity and ALF. (Acetaminophen Hepatotoxicity and Acute Liver Failure, Linda J. Chun, et al., 2009).
[0010] Drug-induced liver injury (DILI) is a common cause of acute liver injury. Paracetamol, also known as acetaminophen, is a widely used antipyretic that has long been established to cause liver toxicity once above therapeutic levels. Hepatotoxicity from paracetamol overdose, whether intentional or nonintentional, is the most common cause of DILI in the United States and remains a global issue. Given the increased prevalence of combination medications in the form of pain relievers and antihistamines, paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity, as evidenced by its contribution to over half of all acute liver failure cases in the United States. This is especially concerning given that, when co-ingested with other medications, the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy. This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on currently available knowledge and treatment options. (Liver injury induced by paracetamol and challenges associated with intentional and unintentional use, Laura Rotundo et al., 2020).
[0011] A transdermal system of paracetamol in infants and children with effects of vehicle formulations on percutaneous penetration is disclosed in the scientific article. Transdermal penetration of the drug was improved by using 4% PEG-40 Stearate and 10% ethanol in the dermal patches in vivo.
[0012] However, the above-mentioned existing routes of administration are not practical in sick adults who often refuse to take the full dose of the medication orally (due to taste or other reasons). Further, none of the existing art talks about the oral usage of acetaminophen in treating alcoholic patients. Therefore, an alternative route of administration may be most useful for adult and alcoholic patients use. This specification recognizes that there is a need for an efficient transdermal administration of APAP. There is also a need for a transdermal drug delivery patch and a method for the manufacture of an adhesive monolithic dispersion membrane pressure-sensitive layer.
[0013] Thus, in view of the above, there is a long-felt need in the healthcare industry to address the described issues.
[0014] Further limitations and disadvantages of conventional and traditional approaches will become apparent to one of ordinary skill in the art through the comparison of described systems with some aspects of the present disclosure, as set forth in the remainder of the present application and with reference to the drawings.

SUMMARY
[0015] A method for the manufacture of an adhesive monolithic dispersion membrane pressure-sensitive layer is provided and shown in and/or described in connection with the figures.
[0016] According to embodiments illustrated herein, there is provided a method for the manufacture of an adhesive monolithic dispersion membrane pressure sensitive layer. The method includes a step of a) mixing 700 grams of water, meglumine, polyethylene glycol 600 (PEG-600), and glycerin till clear to obtain a first mixture. The method includes a step of b) mixing sodium polyacrylic acid salt, dihydroxyaluminium amino acetate, and Sodium carboxymethyl cellulose (sodium CMC) till uniform to obtain a first clear solution and adding the clear solution to the first mixture to obtain a second mixture. The method includes a step of c) heating purified water in a vessel and then adding gelatin, Polyvinylpyrrolidone (pvpk-90), and d-sorbitol powder into the water to obtain a second clear solution, then adding and mixing tartaric acid, titanium dioxide, and kaolin light powder into the second clear solution till uniform without any lumps to obtain bulk and cooling the bulk to room temperature to obtain a third mixture. The method includes a step of d) adding the second mixture to the third mixture and mixing them till uniform viscous gel appears to obtain a solution. The method includes a step of e) dragging the solution on a backing membrane with 3 mm thickness to obtain a sheet and drying the sheet. The method includes a step of: f) cutting the dried sheet to obtain the adhesive monolithic dispersion membrane for the transdermal drug delivery patch.
[0017] In an aspect, the purified water is heated in the vessel up to 60°C.
[0018] In an aspect, the sheet is dried under 80°C for 1 hour and 20 minutes.
[0019] In an aspect, the dried sheet is cut into a 6.2 x 6.2 mm size patch which is equivalent to 500 mg of paracetamol.
[0020] According to embodiments illustrated herein, there is provided a transdermal drug delivery patch that includes a backing membrane, a drug layer, and a release liner. The drug layer stores a drug. The backing membrane supports the drug layer. The release liner is a siliconized Polyethylene terephthalate (PET) liner to allow a user to peel the release liner before using it.
[0021] In an aspect, the transdermal drug delivery patch in combination with the drug is moderately soluble in a plasticizer.
[0022] In an aspect, the drug is paracetamol.
[0023] In an aspect, the drug layer utilizes a plurality of solubility enhancers to improve the loading capacity of the drug.
[0024] In an aspect, the plurality of solubility enhancers comprises Meglumine.
[0025] In an aspect, the drug is dispersed in an adhesive polymer to obtain a medicated adhesive and then the medicated adhesive is spread by solvent casting melted onto a sheet of a drug-impermeable metallic plastic backing or non-woven backing to form a thin drug reservoir layer.
[0026] Accordingly, one advantage of the present inventive subject matter is that the transdermal drug delivery patches are self-contained, discrete dosage forms that when applied to intact skin deliver the drug through the skin at a controlled rate into the systemic circulation.
[0027] Accordingly, one advantage of the present inventive subject matter is that it provides a transdermal drug delivery patch of adhesive monolithic dispersion membrane pressure-sensitive layer.
[0028] Accordingly, one advantage of the present inventive subject matter is that it provides a transdermal drug delivery patch of adhesive monolithic dispersion membrane pressure-sensitive layer.
[0029] Accordingly, one advantage of the present inventive subject matter is that it provides a transdermal drug delivery patch of adhesive dispersion monolithic dispersion membrane pressure sensitive layer.
[0030] Accordingly, one advantage of the present inventive subject matter is that it provides a process for the preparation of transdermal drug delivery patch of adhesive monolithic dispersion membrane pressure sensitive layer.
[0031] These features and advantages of the present disclosure may be appreciated by reviewing the following description of the present disclosure, along with the accompanying figures wherein like reference numerals refer to like parts.

BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The accompanying drawings illustrate the embodiments of methods and other aspects of the disclosure. A person with ordinary skills in the art will appreciate that the illustrated element boundaries (e.g., boxes, groups of boxes, or other shapes) in the figures represent an example of the boundaries of such elements. In some examples, one element may be designed as multiple elements, or multiple elements may be designed as one element. In some examples, an element shown as an internal component of one element may be implemented as an external component in another and vice versa. Furthermore, the elements may not be drawn to scale.
[0033] Various embodiments will hereinafter be described in accordance with the appended drawings, which are provided to illustrate, not limit, the scope, wherein similar designations denote similar elements, and in which:
[0034] FIG. 1 illustrates a flowchart of a method for the manufacture of an adhesive monolithic dispersion membrane pressure-sensitive layer, in accordance with an embodiment of the present invention.
[0035] FIG. 2 illustrates a perspective view of various layers of the transdermal drug delivery patch, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION
[0036] The present disclosure is best understood with reference to the detailed figures and description set forth herein. Various embodiments of the present systems and methods have been discussed with reference to the figures. However, those skilled in the art will readily appreciate that the detailed description provided herein including the figures are presented for explanatory purposes and the embodiments extend beyond the currently described embodiments. For instance, the teachings and results presented in any particular described application may yield multiple alternative approaches and may be implemented in any suitable manner.
[0037] The described embodiments may be implemented manually, automatically, and/or a combination of thereof. The term “method” refers to manners, means, techniques, and procedures for accomplishing any task including, but not limited to, those manners, means, techniques, and procedures either known to the person skilled in the art or readily developed from existing manners, means, techniques and procedures by practitioners of the art to which the embodiments pertains. Persons skilled in the art will envision many other possible variations that are within the scope of the claimed subject matter.
[0038] The present disclosure provides a transdermal drug delivery patch that provides a sustained release (SR) dosage form intended for transdermal usage and is indicated for the treatment of primary fever, mild to moderate pain, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and also treatment for acute migraine symptoms.
[0039] FIG. 1 illustrates a flowchart 100 of a method for the manufacture of an adhesive monolithic dispersion membrane pressure-sensitive layer, in accordance with an embodiment of the present invention. The method includes a step 102 of a) mixing 700 grams of water, meglumine, polyethylene glycol 600 (PEG-600), and glycerin till clear to obtain a first mixture. The method includes a step 104 of b) mixing sodium polyacrylic acid salt, dihydroxyaluminium amino acetate, and sodium carboxymethyl cellulose (sodium CMC) till uniform to obtain a first clear solution and adding the clear solution to the first mixture to obtain a second mixture. The method includes a step 106 of c) heating purified water in a vessel and then adding gelatin, Polyvinylpyrrolidone (pvpk-90), and d-sorbitol powder into the water to obtain a second clear solution, then adding and mixing tartaric acid, titanium dioxide, and kaolin light powder into the second clear solution till uniform without any lumps to obtain bulk and cooling the bulk to room temperature to obtain a third mixture. The method includes a step 108 of d) adding the second mixture to the third mixture and mixing them till uniform viscous gel appears to obtain a solution. The method includes a step 110 of e) dragging the solution on a backing membrane with 3 mm thickness to obtain a sheet and drying the sheet. The method includes a step 112 of f) cutting the dried sheet to obtain the adhesive monolithic dispersion membrane for the transdermal drug delivery patch. In an embodiment, the purified water is heated in the vessel up to 60°C. In an embodiment, the sheet is dried under 80°C for 1 hour and 20 minutes. In an embodiment, the dried sheet is cut into a 6.2 x 6.2 mm size patch which is equivalent to 500 mg of paracetamol.
[0040] FIG. 2 illustrates a perspective view of various layers of the transdermal drug delivery patch 200, in accordance with an embodiment of the present invention. The transdermal drug delivery patch 200 includes a backing membrane 202, a drug layer 204, and a release liner 206. The backing membrane 202 supports the drug layer 204. In an embodiment, the backing membrane 202 is a non-woven backing membrane, or backing film or layer that supports the transdermal drug delivery patch 200 and has a limited strength of the drug layer 204. The non-woven backing membrane is used during the development of the transdermal drug delivery patch 200 which is thick and supports the drug layer 204. This non-woven backing membrane is economical when compared to the various branded backing membranes.
[0041] The drug layer 204 stores a drug. In an embodiment, the drug is paracetamol. In an embodiment, the drug layer 204 is made using a reservoir technology, where more drugs can be loaded i.e equivalent to 500mg of paracetamol. The method of the present invention uses solubility enhancers such as Meglumin to improve the drug loading capacity. The release liner 206 is a siliconized Polyethylene terephthalate (PET) liner to allow a user to peel the release liner 206 before using it.
[0042] In an embodiment, the transdermal drug delivery patch 200 in combination with the drug is moderately soluble in a plasticizer. In an embodiment, the drug layer 204 utilizes a plurality of solubility enhancers to improve the loading capacity of the drug. In an embodiment, the plurality of solubility enhancers comprises Meglumine. In an embodiment, the drug is dispersed in an adhesive polymer to obtain a medicated adhesive and then the medicated adhesive is spread by solvent casting melted onto a sheet of a drug-impermeable metallic plastic backing or non-woven backing to form a thin drug reservoir layer.
[0043] According to an embodiment herein, the transdermal drug delivery patch may include a plurality of excipients such as plasticizers and solvents, an active pharmaceutical ingredient (API), a thickening agent, and a humectant. In an embodiment, the active pharmaceutical ingredient (API) is acetaminophen or paracetamol. In an embodiment, the plasticizer is selected from PEG-400, glycerine, and propylene glycol. Plasticizers are generally non-volatile organic liquids or solids with low melting temperatures and when added to polymers, they cause changes in definite physical and mechanical characteristics of the material The main reasons for adding plasticizers to polymers, improving flexibility and processability are counted, upon the addition of plasticizer, flexibilities of polymer macromolecules or macromolecular segments increase as a result of the loosening of tightness of intermolecular forces. Plasticizers are low molecular weight resins or liquids, which cause a reduction in polymer chain secondary bonding, forming secondary bonds with the polymer chains instead Major solvents used in this formulation are water, ethanol, and PEG.
[0044] In an embodiment, the thickening agent is selected from HPMC E15 or polyvinyl alcohol. In an embodiment, the solvent is selected from Water for HPMC, ethanol, and water for PVA. In an embodiment, the humectant is glycerine. In an embodiment, the transdermal drug delivery patch delivers a controlled/sustained release of active pharmaceutical ingredients to a subject/animal/medium/skin membrane for predefined hours or days. In an embodiment, the transdermal drug delivery patch includes a skin permeation enhancer selected from ethanol, oleic acid, or menthol. In an embodiment, the skin permeation enhancer is present in 5% per transdermal drug delivery patch. In an embodiment, the weight ratio of active pharmaceutical ingredients to plasticizers is 1:4.5.
[0045] According to an embodiment, the API is solubilized in high concentration, by using PEG-400/600/800/1000 in combination with adhesive polyisobutylene. The present invention is based upon a discovery that certain adhesive-based drug-containing systems and transdermal patch systems are employed utilizing polyisobutylene and a plasticizer (PEG) for the polyisobutylene in combination with a drug that is moderately soluble in that plasticizer and which patches can be relatively simple in that they can be provided in the form of a monolithic patch system. A monolithic system means a system in which the skin contacts the adhesive system, and the drug itself is combined and applied to the backing membrane, covered by the release liner, and is essentially ready for use.
[0046] According to an embodiment herein, the transdermal drug delivery patches are produced as paracetamol transdermal patch 500 mg. The paracetamol transdermal patch 500 mg was developed as a sustain-release dosage form and is indicated for the treatment of fever, mild to moderate pain, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and also treatment for acute migraine symptoms. Based on the prior experience and need for the formulation, a direct mixing and blending process was selected for Paracetamol Transdermal Patch 500 mg. The risk assessment approaches were applied throughout the development of the drug product to identify potential risks in the formulation and process variations, and also to determine what studies were necessary to achieve product quality. By understanding the risk assessment, a control strategy is developed.
[0047] The control strategy of producing the transdermal drug delivery patches includes the critical process parameters that were identified as potential risk variables during the initial risk assessments. The control strategy is also applied for in-process controls of the manufacturing process and finished product specifications.
[0048] Thus, the present invention provides transdermal drug delivery patches that are self-contained that have various advantages such as improved patient compliance, the ability of site targeting, non-invasiveness, and avoiding the first-pass effect. Further, the transdermal drug delivery patches of the present invention are superior in terms of safety and convenience. Hence, it is the most preferred drug delivery system over oral and invasive conventional drug delivery systems. The transdermal drug delivery patch may be of an active or a passive design providing an alternative route for administering medicaments.
[0049] Transdermal delivery not only provides controlled and constant administration of the drug but also allows continuous input of drugs with a short biological half-life and eliminates pulsed entry into systemic circulations, which may result in undesirable side effects. Further, the present invention provides a transdermal drug delivery patch of adhesive monolithic dispersion membrane pressure sensitive layer. Furthermore, the present invention provides a transdermal drug delivery patch of adhesive monolithic dispersion membrane pressure sensitive layer, wherein an active pharmaceutical ingredient is present in the amount of 200 mg to 1000 mg per transdermal drug delivery patch. Further, the present invention provides a transdermal drug delivery patch of adhesive dispersion monolithic dispersion membrane pressure sensitive layer, wherein the transdermal drug delivery patch delivers a controlled/sustained release of active pharmaceutical ingredient to a subject/animal/medium/skin membrane for a period of X hours or days.
[0050] A person skilled in the art will understand that the transdermal drug delivery patch and method for the manufacture of an adhesive monolithic pressure-sensitive layer are described herein for illustrative purposes and should not be construed to limit the scope of the disclosure.
[0051] A person with ordinary skills in the art will appreciate that the methods have been illustrated and explained to serve as examples and should not be considered limiting in any manner. It will be further appreciated that the variants of the above-disclosed system elements, modules, and other features and functions, or alternatives thereof, may be combined to create other different apparatuses, systems, or applications.
[0052] While the present disclosure has been described with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope. Therefore, it is intended that the present disclosure not be limited to the particular embodiment disclosed, but that the present disclosure will include all embodiments falling within the scope of the appended claims.
, Claims:CLAIMS

I/We claim:

1. A method for the manufacture of an adhesive monolithic dispersion membrane pressure-sensitive layer, comprising:
a) mixing 700 grams of water, meglumine, polyethylene glycol 600 (PEG-600), and glycerin till clear to obtain a first mixture;
b) mixing sodium polyacrylic acid salt, dihydroxyaluminium amino acetate, and Sodium carboxymethyl cellulose (sodium CMC) till uniform to obtain a first clear solution and adding the clear solution to the first mixture to obtain a second mixture;
c) heating purified water in a vessel and then adding gelatin, Polyvinylpyrrolidone (pvpk-90), and d-sorbitol powder into the water to obtain a second clear solution, then adding and mixing tartaric acid, titanium dioxide, and kaolin light powder into the second clear solution till uniform without any lumps to obtain bulk and cooling the bulk to room temperature to obtain a third mixture;
d) adding the second mixture to the third mixture and mixing them till uniform viscous gel appears to obtain a solution;
e) dragging the solution on a backing membrane with 3 mm thickness to obtain a sheet and drying the sheet; and
f) cutting the dried sheet to obtain the adhesive monolithic dispersion membrane for the transdermal drug delivery patch.

2. The method according to claim 1, wherein the purified water is heated in the vessel up to 60°C.

3. The method according to claim 1, wherein the sheet is dried under 80°C for 1 hour and 20 minutes.

4. The method according to claim 1, wherein the dried sheet is cut into a 6.2 x 6.2 mm size patch which is equivalent to 500 mg of paracetamol.

5. A transdermal drug delivery patch, comprising:
a backing membrane;
a drug layer to store a drug, wherein the backing membrane supports the drug layer; and
a release liner, wherein the release liner is a siliconized Polyethylene terephthalate (PET) liner to allow a user to peel the release liner before using.

6. The transdermal drug delivery patch according to claim 5 in combination with the drug is moderately soluble in a plasticizer.

7. The transdermal drug delivery patch according to claim 5, wherein the drug is paracetamol.

8. The transdermal drug delivery patch according to claim 5, wherein the drug layer utilizes a plurality of solubility enhancers to improve the loading capacity of the drug.

9. The transdermal drug delivery patch according to claim 8, wherein the plurality of solubility enhancers comprises Meglumine.

10. The transdermal drug delivery patch according to claim 5, wherein the drug is dispersed in an adhesive polymer to obtain a medicated adhesive and then the medicated adhesive is spread by solvent casting melted onto a sheet of a drug impermeable metallic plastic backing or non-woven backing to form a thin drug reservoir layer.

Dated February 11, 2023
Chaitanya Rajendra Zanpure
Agent for Applicant
IN-PA-2282